A Deeper Look into the Cellular Caves: Caveolins, Cavins and Popdc Proteins in Cardioprotection

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Can Justin Kiessling, PhD
Kevin Ashton, PhD


 Cardioprotection is a promising novel therapeutic approach for the treatment of ischemic heart disease (IHD). Various cardioprotective methods such as ischemic, anesthetic and G-protein-coupled-receptor (GPCR) based preconditioning have been shown to be reliant on the presence of unique regions in the sarcolemma termed caveolae. Caveolae compartmentalize and concentrate various classes of signaling molecules involved in stress-resistance, including important mediators of cardioprotection such as receptor tyrosine kinases, GPCRs and their subunits. The unique morphology of caveolae arises from the expression of its coat proteins belonging to those of caveolin, cavin and Popeye domain-containing (Popdc) family of proteins. As outlined in this review, although contributions of caveolins (especially Caveolin-3) in cardioprotection are relatively well-characterized, recent studies indicate that members of the cavins and the Popdc family of proteins are also crucial for sarcolemmal caveolae formation, an important determinant of ischemia-reperfusion (I-R) injury. In this article, we discuss the evidence for the involvement of caveolins, cavins and Popdc family of proteins in cardioprotective signaling and the essential role of caveolae in age-related reduction of cardioprotective signaling. Age-related changes in sarcolemmal makeup as evidenced by down-regulation of caveolins in several types of tissues is linked to decreased stress-resistance, and may help partially explain the refractoriness to protective stimuli in the aging heart. Hence, a greater understanding of the role of caveolae and its coat proteins as briefly outlined here may help facilitate the development of cardioprotective strategies as despite the decades of research, currently there are no effective treatments for limiting I-R injury. Since many of the existing experimental cardioprotective interventions such as the clinically feasible post-conditioning method is reliant on caveolae, methods that enhance or restore caveolae in the aged heart may be a viable therapeutic strategy for the treatment ischemic heart disease.


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Kiessling CJ, Ashton K. A Deeper Look into the Cellular Caves: Caveolins, Cavins and Popdc Proteins in Cardioprotection. BKK Med J [Internet]. 2017 Feb. 20 [cited 2023 Dec. 8];13(1):77. Available from: https://he02.tci-thaijo.org/index.php/bkkmedj/article/view/221803
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1. World Health Organization. Non-communicable Diseases Country Profles, 2014. (Accessed October 22, 2016, at http://www.who.int/nmh/countries/tha_en.pdf.)
2. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124-36.
3. Kidd MW, Reichelt ME, Peart JN, et al. Caveolin and the aged myocardium. FASEB J 2010;4:819-2.
4. Senju Y, Itoh Y, Takano K, et al. Essential role of PACSIN2/ syndapin-II in caveolae membrane sculpting. J Cell Sci 2011;124:2032-40.
5. Morén B, Shah C, Howes MT, et al. EHD2 regulates caveolar dynamics via ATP-driven targeting and oligomerization. Mol Biol Cell 2012;23:1316-29.
6. nsel PA, Head BP, Patel HH, et al. Compartmentation of G-protein-coupled receptors and their signalling components in lipid rafts and caveolae. Biochem Soc Trans 2005:33;1131-4.
7. acellular Caveolin-3-associated Microdomains in Adult Cardiac Myocytes. J Biol Chem 2005;280:31036-44.
8. Tsutsumi YM, Horikawa YT, Jennings MM, et al. Cardiacspecifc overexpression of caveolin-3 induces endogenous cardiac protection by mimicking ischemic preconditioning. Circulation 2008;118:1979-88.
9. Patel HH, Head BP, Petersen HN, et al. Protection of adult rat cardiac myocytes from ischemic cell death: role of caveolar microdomains and delta-opioid receptors. Am J Physiol Heart Circ Physiol 2006;291:H344-50.
10. Razani B, Woodman SE, Lisanti MP. Caveolae: From Cell Biology to Animal Physiology. Pharmacol Rev 2002;54:431-67.
11. Lasley, RD. Adenosine Receptors and Membrane Microdomains. Biochim Biophys Act 2012;1808:1284-9.
12. Monaghan-Benson E, Mastick CC, McKeown-Longo PJ. A dual role for caveolin-1 in the regulation of fbronectin matrix assembly by uPAR. J Cell Sci 2008;121:3693-703.
13. Ju H, Venema VJ, Liang H, Harris MB, et al. Bradykinin activates the Janus-activated kinase/signal transducers and activators of transcription (JAK/STAT) pathway in vascular endothelial cells: localization of JAK/STAT signalling proteins in plasmalemmal caveolae. Biochem J 2000;351(Pt 1):257-64.
14. arcía-Cardeña G, Martasek P, Masters BS, et al. Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional signifcance of the nos caveolin binding domain in vivo. J Biol Chem 1997;272:25437-40.
15. Chow AK, Cena J, El-Yazbi AF, et al. Caveolin-1 inhibits matrix metalloproteinase-2 activity in the heart. J Mol Cell Cardiol 2007;42:896-901
16. Rothberg KG, Heuser JE, Donzell WC, et al. Caveolin, a protein component of caveolae membrane coats.Cell 1992;68:673-82.
17. Schlegel A, Pestell RG, Lisanti MP. Caveolins in cholesterol trafficking and signal transduction:implications for human disease.Front Biosci 2000;1:D929-37.
18. Drab M, Verkade P, Elger M, et al. Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice.Science 2001;293:2449-52.
19. Park DS, Cohen AW, Frank PG, et al. Caveolin-1 null (-/-) mice show dramatic reductions in life span.Biochemistry 2003;42:15124-31
20. Park DS, Woodman SE, Schubert W, et al. Caveolin-1/3 Double-Knockout Mice Are Viable, but Lack Both Muscle and Non-Muscle Caveolae, and Develop a Severe Cardiomyopathic Phenotype. Am J Pathol 2002;160:2207-17.
21. Kang-Decker N, Cao S, Chatterjee S, et al. Nitric oxide promotes endothelial cell survival signaling through S-nitrosylation and activation of dynamin-2.J Cell Sci 2007;120:492-501.
22. Patel HH, Tsutsumi YM, Head BP, et al. Mechanisms of cardiac protection from ischemia/reperfusion injury: a role
for caveolae and caveolin-1.FASEB 2007;21:1565-74.
23. Jasmin JF, Rengo G, Lymperopoulos A, et al. Caveolin-1 defciency exacerbates cardiac dysfunction and reduces survival in mice with myocardial infarction. Am J Physiol Heart Circ Physiol 2011;300:H1274-81.
24. Young LH, Ikeda Y, Lefer AM. Caveolin-1 peptide exerts cardioprotective effects in myocardial ischemia-reperfusion via nitric oxide mechanism. Caveolin-1 peptide exerts cardioprotective effects in myocardial ischemia-reperfusion via nitric oxide mechanism. Am J Physiol Heart Circ Physiol 2001;280:H2489-95.
25. Bucci M, Gratton JP, Rudic RD, et al. In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation.Nat Med 2000;6:1362-7.
26. Shivshankar P, Halade GV, Calhoun C, et al. Caveolin-1 deletion exacerbates cardiac interstitial fbrosis by promoting M2 macrophage activation in mice after myocardial infarction. J Mol Cell Cardiol 2014;76:84-93.
27. Miyasato SK, Loeffler J, Shohet R, et al. Caveolin-1 modulates TGF-β1 signaling in cardiac remodeling. Matrix Biol 2011;30:318-29.
28. Del Pozo MA, Balasubramanian N, Alderson NB, et al. Phospho-caveolin-1 mediates integrin-regulated membrane domain internalization.Nat Cell Biol 2005;7:901-8.
29. Corrotte M, Almeida PE, Tam C, et al. Caveolae internalization repairs wounded cells and muscle fbers. Elife 2013;2:e00926.
30. Kang-Decker N, Cao S, Chatterjee S, et al. Nitric oxide promotes endothelial cell survival signaling through S-nitrosylation and activation of dynamin-2.J Cell Sci 2007;120:492-501.
31. Bernatchez PN, Sharma A, Kodaman P, et al. Myoferlin is critical for endocytosis in endothelial cells. Am J Physiol Cell Physiol 2009;297:C484-92.
32. Cheng JP, Mendoza-Topaz C, Howard G, et al. Caveolae protect endothelial cells from membrane rupture during increased cardiac output.J Cell Biol 2015;211:53-61.
33. Ortiz-Pérez JT, Lee DC, Meyers SN, et al. Determinants of myocardial salvage during acute myocardial infarction: evaluation with a combined angiographic and CMR myocardial salvage index.JACC Cardiovasc Imaging 2010;3:491-500.
34. Lund GK, Stork A, Muellerleile K, et al. Prediction of left ventricular remodeling and analysis of infarct resorption
in patients with reperfused myocardial infarcts by using contrastenhanced MR imaging.Radiology 2007;245:95-102.
35. Lund GK, Stork A, Muellerleile K, et al. Prediction of left ventricular remodeling and analysis of infarct resorption
in patients with reperfused myocardial infarcts by using contrastenhanced MR imaging.Radiology 2007;245:95-102.
36. Liu L, Brown D, McKee M, et al. Deletion of Cavin/PTRF causes global loss of caveolae, dyslipidemia, and glucose intolerance.Cell Metab 2008;8:310-7.
37. Gazzerro E, Sotgia F, Bruno C, et al. Caveolinopathies: from the biology of caveolin-3 to human diseases.Eur J Hum Genet 2010;18:137-45.
38. Horikawa YT, Patel, HH, Tsutsumi YM, et al. Caveolin-3 expression and caveolae are required for isoflurane-induced cardiac protection from hypoxia and ischemia/reperfusion injury.J Mol Cell Cardiol 2008;44:123-30.
39. Horikawa YT, Patel, HH, Tsutsumi YM, et al. Caveolin-3 expression and caveolae are required for isoflurane-induced cardiac protection from hypoxia and ischemia/reperfusion injury.J Mol Cell Cardiol 2008;44:123-30.
40. Tsutsumi YM, Kawaraguchi Y, Horikawa YT, et al. Role of caveolin-3 and glucose transporter-4 in isoflurane-induced delayed cardiac protection.Anesthesiology 2010;112:1136-45.
41. Tsutsumi YM, Kawaraguchi Y, Niesman, IR, et al. Opioidinduced preconditioning is dependent on caveolin-3 expression.Anesth Analg 2010;111:1117-21.
42. Massion PB, Dessy C, Desjardins F, et al. Cardiomyocyterestricted overexpression of endothelial nitric oxide synthase (NOS3) attenuates beta-adrenergic stimulation and reinforces vagal inhibition of cardiac contraction. Circ 2004;110:2666-72.
43. Sun J, Kohr MJ, Nguyen T, et al. Disruption of caveolae blocks ischemic preconditioning-mediated S-nitrosylation of mitochondrial proteins.Antioxid Redox Signal 2012;16:45-56.
44. Sun J, Picht E, Ginsburg KS, et al. Hypercontractile Female Hearts Exhibit Increased S-Nitrosylation of the L-Type Ca2+ Channel α1 Subunit and Reduced Ischemia/Reperfusion Injury.Circ Res 2006;98:403-11.
45. Jennings RB, Steenbergen C Jr, Kinney RB, et al. Comparison of the effect of ischemia and anoxia on the sarcolemma of the dog heart.Eur Heart J 1983;4:123-37.
46. Cipta S, Tsutsumi YM, Kidd MW, et al. Dynamin and caveo lae in cardiac ischemic preconditioning. FASEB J 2009;23:LB381.
47. Hernández-Deviez DJ, Howes MT, Laval SH, et al. Caveolin regulates endocytosis of the muscle repair protein, dysferlin. J Biol Chem 2008;283:6476-88.
48. Matsuda C, Hayashi YK, Ogawa M, et al. The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle. Hum Mol Genet 2001;10:1761-6.
49. Cai C, Masumiya H, Weisleder N, et al. MG53 nucleates assembly of cell membrane repair machinery. Nat Cell Biol 2009;11:56-64.
50. Wang X, Xie W, Zhang Y, et al. Cardioprotection of ischemia/reperfusion injury by cholesterol-dependent MG53-mediated membrane repair.Circ Res 2010;107:76-83.
51. Breen MR, Camps M, Carvalho-Simoes F, et al. Cholesterol depletion in adipocytes causes caveolae collapse concomitant with proteosomal degradation of cavin-2 in a switch-like fashion.PLoS One 2012;7:e34516.
52. Kassan A, Pham U, Nguyen Q, et al. Caveolin-3 plays a critical role in autophagy after ischemia-reperfusion. Am J Physiol Cell Physiol 2016;00147.
53. Bastiani M, Liu L, Hill MM, et al. MURC/Cavin-4 and cavin family members form tissue-specifc caveolar complexes. J Cell Biol 2009;185: 259-73.
54. Briand N, Dugail I, Le LS. Cavin proteins: New players in the caveolae feld. Biochimie 2010;93:71-7.
55. Shumway SD, Maki M, Miyamoto S. The PEST domain of IkappaBalpha is necessary and suffcient for in vitro degradation by mu-calpain.J Biol Chem 1999;274:30874-81.
56. Reverte CG, Ahearn MD, Hake LE. CPEB degradation during Xenopus oocyte maturation requires a PEST domain and the 26S proteasome.Dev Biol 2001;231:447–58.
57. Parton RG, del Pozo MA. Caveolae as plasma membrane sensors, protectors and organizers. Nat Rev Mol Cell Biol 2013;14:98-112.
58. McMahon KA, Zajicek H, Li WP, et al. SRBC/cavin-3 is a caveolin adapter protein that regulates caveolae function. EMBO J 2009;28:1001-15.
59. Naito D, Ogata T, Hamaoka T, et al. The coiled-coil domain of MURC/cavin-4 is involved in membrane traffcking of caveolin-3 in cardiomyocytes.Am J Physiol Heart Circ Physiol 2015;309:H2127-36.
60. Jansa P, Mason SW, Hoffmann-Rohrer U, et al. Cloning and functional characterization of PTRF, a novel protein which induces dissociation of paused ternary transcription complexes.EMBO J 1998;17:2855–2864.
61. Vinten J, Johnsen AH, Roepstorff P, et al. Identifcation of a major protein on the cytosolic face of caveolae. Biochim Biophys Acta 2005;1717:34-40.
62. Hansen CG, Shvets E, Howard G, et al. Deletion of cavin genes reveals tissue-specifc mechanisms for morphogenesis of endothelial caveolae.Nat Commun 2013;4:1831.
63. Kasahara T, Ogata T, Maruyama N, et al. PTRF/Cavin-1 Knock-out Mice Develop a Progressive Cardiomyopathy with ERK1/2 Hyperactivation and Caveolin-3 Reduction.Circ 2014;130:A13847
64. Hill MM, Bastiani M, Luetterforst R, et al. PTRF-Cavin, a conserved cytoplasmic protein required for caveola formation and function.Cell 2008;132:113-24.
65. Norman R, Ross C, Trelfa L, et al. Remodelling of the veolar domain in models of right and left heart failure in the rat. Proc Physiol Soc 2014;31:PCA039.
66. aniguchi T, Maruyama N, Ogata T, et al. PTRF/Cavin-1 Defciency Causes Cardiac Dysfunction Accompanied by Cardiomyocyte Hypertrophy and Cardiac Fibrosis.PLoS One 2016;11:e0162513.
67. Hayashi YK, Matsuda C, Ogawa M, et al. Human PTRF mutations cause secondary defciency of caveolins resulting in muscular dystrophy with generalized lipodystrophy.J Clin Invest 2009;119:2623-33.
68. Zhu H, Lin P, De G, et al. Polymerase transcriptase release factor (PTRF) anchors MG53 protein to cell injury site for initiation of membrane repair.J Biol Chem 2011;286:12820-4.
69. Cao CM, Zhang Y, Weisleder N, et al. MG53 constitutes a primary determinant of cardiac ischemic preconditioning. Circulation 2010;121:2565-74.
70. Alcalay Y, Hochhauser E, Kliminski V, et al. Popeye domain containing 1 (Popdc1/Bves) is a caveolae-associated protein involved in ischemia tolerance.PLoS One 2013;8:e71100.
71. Andrée B, Fleige A, Arnold HH, et al. Mouse Pop1 is required for muscle regeneration in adult skeletal muscle. Mol Cell Biol 2002;22:1504-12.
72. Brand T, Simrick SL, Poon KL, et al. The cAMP-binding Popdc proteins have a redundant function in the heart. Biochem Soc Trans 2014;42:295-301.
73. Schindler RF, Poon KL, Simrick S, et al. The Popeye domain containing genes: essential elements in heart rate control. Cardiovasc Diagn Ther 2012;2:308-19.
74. Froese A, Breher SS, Waldeyer C, et al. Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice. J Clin Invest 2012;122:1119- 30.
75. Hager HA, Roberts RJ, Cross EE, et al. Identification of a novel Bves function: regulation of vesicular transport. EMBO J 2010;29:532-45.
76. Schindler RF, Scotton C, Zhang J, et al. POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking. J Clin Invest 2016;126:239-53.
77. Wu M, Li Y, He X, et al. Mutational and functional analysis of the BVES gene coding region in Chinese patients with non-syndromic tetralogy of Fallot. Int J Mol Med 2013;31:899- 903.
78. Tan N, Chung MK, Smith JD, et al. Weighted gene coexpression network analysis of human left atrial tissue identifies gene modules associated with atrial fibrillation. Circ Cardiovasc Genet 2013;6:362-71.
79. Shaw RM, Colecraft HM. L-type calcium channel targeting and local signalling in cardiac myocytes. Cardiovasc Res 2013;98:177-86.
80. Lo HP, Nixon SJ, Hall TE, et al. The caveolin-cavin system plays a conserved and critical role in mechanoprotection of skeletal muscle. J Cell Biol 2015;210:833-49.
81. Gingold-Belfer R, Bergman M, Alcalay Y, et al. Popeye domain-containing 1 is down-regulated in failing human hearts. Int J Mol Med 2011;27:25-31.
82. Feiner EC, Chung P, Jasmin JF, et al. Left ventricular dysfunction in murine models of heart failure and in failing human heart is associated with a selective decrease in the expression of caveolin-3. J Card Fail 2011;17:253-63.
83. Kirchmaier BC, Poon KL, Schwerte T, et al. The Popeye domain containing 2 (popdc2) gene in zebrafish is required for the heart and skeletal muscle development. Dev Biol 2012;362:348-450.
84. Wang X, Tucker NR, Rizki G, et al. Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures. Elife 2016;e10557.
85. Luo D, Lu ML, Zhao GF, et al. Reduced Popdc3 expression correlates with high risk and poor survival in patients with gastric cancer. World J Gastroenterol 2012;18:2423-9.
86. Peart JN, Pepe S, Reichelt ME, et al. Dysfunctional survival-signaling and stress-intolerance in aged murine and human myocardium. Exp Gerontol 2014;50:72-81.
87. Schilling JM, Patel, HH. Non-canonical roles for caveolin in regulation of membrane repair and mitochondria: implications for stress adaptation with age. J Physiol 2015;594:4581-9.
88. Lowalekar SK, Cristofaro V, Radisavljevic ZM, et al. Loss of bladder smooth muscle caveolae in the aging bladder. Neurourol Urodyn 2012;31:586-92.
89. Head BP, Peart JN, Panneerselvam M, et al. Loss of caveolin-1 accelerates neurodegeneration and aging. PLoS One 2010;5:15697.
90. Barrientos G, Llanos P, Hidalgo J, et al. Cholesterol removal from adult skeletal muscle impairs excitation-contraction coupling and aging reduces caveolin-3 and alters the expression of other triadic proteins. C Front Physiol 2015;6:105.
91. Headrick JP, Willems L, Ashton KJ, et al. Ischaemic tolerance in aged mouse myocardium: the role of adenosine and effects of A1 adenosine receptor overexpression. J Physiol 2003;549:823-33.
92. Peart JN, Gross ER, Headrick JP, et al. Impaired p38 MAPK/ HSP27 signaling underlies aging-related failure in opioidmediated cardioprotection. J Mol Cell Cardiol 2007;42:972-80.
93. See Hoe LE, Schilling JM, Tarbit E, et al. Sarcolemmal cholesterol and caveolin-3 dependence of cardiac function, ischemic tolerance, and opioidergic cardioprotection. Am J Physiol Heart Circ Physiol 2014;307:H895-903.
94. Horikawa YT, Panneerselvam M, Kawaraguchi Y, et al. Cardiac-specific overexpression of caveolin-3 attenuates cardiac hypertrophy and increases natriuretic peptide expression and signalling. J Am Coll Cardiol 2011;57:2273-83.
95. Fridolfsson HN, Reichelt ME, Peart JN, et al. Role of caveolin-3 and mitochondria in protecting the aged myocardium. FASEB J 2012;26:864.16.
96. See Hoe L, May LT, Headrick JN, et al. Sarcolemmal dependence of cardiac protection and stress-resistance: roles in aged or diseased hearts. Br J Pharmacol 2016;173:2966-91.
97. Schilling JM, Roth DM, Patel HH. 2015. Caveolins in cardioprotection - translatability and mechanisms. Br J Pharmacol 2015;172:2114-25.
98. Rosello X, Yellon DM. Cardioprotection: The Disconnect Between Bench and Bedside. Circulation 2016;134:574-75.
99. Hausenloy DJ, Yellon DM. Ischaemic conditioning and reperfusion injury. Nat Rev Cardiol 2016;13:193-209.
100. Chira S, Jackson CS, Oprea J, et al. Progresses towards safe and efficient gene therapy vectors. Oncotarget 2015;6:30675–30703.
101. Kidd MW, Tsutsumi YM, Niesman IR, et al. In vivo caveolin-3 adenoviral gene delivery restores caveolin-3 protein expression and caveolae in cardiac myocytes of caveolin-3 knockout mice. FASEB J 2008;22:1180.2.
102. Shen J, Lee W, Chen J, et al. Caveolin-3 Peptide Protects Cardiomyocytes from Apoptotic Cell Death via Preserving Superoxide Dismutase Activity and Inhibiting Caspase-3 Activation under Hypoxia-reoxygenation. AJBMS 2011;3:126-44.
103. Sharma A, Leung C, Stefanovic N, et al. Therapeutic use of eNOS/Caveolin-1 antagonistic peptides for endothelial dysfunction and atherogenesis. FASEB J 2013;27:672.4.
104. Nishi M, Ogata T, Nakanishi N, et al. MURC/Cavin-4 Deficiency Reduces Infarct Size and Preserves Cardiac Function in a Mouse Model of Ischemia-Reperfusion Injury. Circulation 2016;134:A12941.
105. Maruyama N, Ogata T, Nakanishi N, et al. SDPR/Cavin-2 Modulates Akt Signaling Involved in Regulation of Hypertrophy and Apoptosis in Cardiomyocytes. Circulation 2014;130:15598.
106. Han B, Copeland CA, Tiwari A, et al. Assembly and Turnover of Caveolae: What Do We Really Know? Front Cell Dev Biol 2016:4;68.